Leptin is an adipocyte hormone that provides the central nervous system as well as peripheral organs with a signal of nutritional status. Leptin has important effects in the regulation of endocrine function. Leptin treatment of starved rodents corrects the effects of starvation or immaturity on the pituitary-adrenal, pituitary-gonadal, and pituitary-thyroid endocrine axes. However, there are important differences in metabolism and leptin biology of human leptin. The results obtained by studies of leptin treatment of non-leptin treatment of non-leptin deficient subjects are confounded by the pulsatile and highly variable endogenous leptin production, as well as by the fact that the transport of leptin into the brain is saturable. Moreover, leptin has not been widely available for endocrine investigation. The P.I. of this application has successfully worked with the only three adult individuals who have been identified anywhere in the world with a functional leptin gene mutation, of Mendelian recessive inheritance. Those patients are members of a large, extended, and highly consanguineous pedigree. They are morbidity obese and present with endocrine dysfunction. To test the hypothesis that leptin contributes to regulation of the minute-to-minute dynamics of human endocrine function, we propose a series of prospective, longitudinal, rapid-sampled 24-h endocrine studies during the course of leptin replacement therapy in those patients. The confirmation of our working hypotheses has two implications. For the understanding of biology, it will indicate that leptin, the product of a disperse mass of peripheral fat cells, contributes to regulate a key function of t he central nervous system which is endocrine homeostasis. Additionally, the proposed studies may identify novel sites of leptin action that may represent novel therapeutic targets in the treatment of human disease.